As one of the most common and fatal forms of hematopoietic malignancies, acute myeloid leukemia (AML) is frequently associated with diverse chromosome translocations (e.g. t(11q23)/MLL-rearrangements, t(15; 17)/PML-RARA and t(8;21)/AML1-ETO) and molecular abnormalities (e.g. internal tandem duplications of FLT3 (FLT3-ITD) and mutations in nucleophosmin (NPM1c+))1. Despite intensive chemotherapies, the majority of patients with AML fail to survive longer than 5 years2, 3. Thus, development of effective therapeutic strategies based on a better understanding of the molecular mechanisms underlying the pathogenesis of AML is urgently needed.
MicroRNAs (miRNAs) are a class of small, non-coding RNAs that post-transcriptionally regulate gene expression4. Individual miRNAs may play distinct roles in cancers originating from different tissues or even from different lineages of hematopoietic cells4. It is unclear whether a single miRNA can play distinct roles between malignancies originating from the same hematopoietic lineage, such as de novo AML and myelodysplastic syndrome (MDS). Although around 30% of MDS cases transform to AML, the genetic and epigenetic landscapes of MDS or MDS-derived AML are largely different from those of de novo AML5, 6. For example, it is known that MDS and MDS-derived AML are more responsive to hypomethylating agents than de novo AML7. The molecular mechanisms underlying the distinct pathogenesis and drug response between MDS (or MDS-derived AML) and de novo AML remain unclear.
The ten-eleven translocation (Tet1/2/3) proteins play critical transcriptional regulatory roles in normal developmental processes as activators or repressors8, 9, 10 ENREF 5. In contrast to the frequent loss-of-function mutations and tumor-suppressor role of TET2 observed in hematopoietic malignancies11, 12, 13, the present investigators recently reported that TET1 plays an essential oncogenic role in MLL-rearranged AML where it activates expression of homeobox genes14. However, it is unknown whether TET1 can also function as a transcriptional repressor in cancer. Moreover, Tet1-mediated regulation of miRNA expression has rarely been studied10.
Investigation of Tet1-mediated regulation of miRNA expression provides a novel pathway for addressing the urgent need for additional and/or complementary treatments for AML.